Ursolic Acid Inhibits Breast Tumor Growth and Angiogenesis through Suppression the Expression of Multiple Adhesion Factors

Abstract

Ursolic acid (UA), a natural pentacyclic triterpenoid, has been reported to exert anti-cancer and anti-angiogenic effects. However, its role in suppressing breast cancer metastasis through modulation of endothelial function and tumor microcirculation remains to be fully elucidated. In this study, we investigated the anti-tumor and anti-angiogenic effects of UA using both in vitro assays and an orthotopic mouse model of breast cancer. Cell viability, apoptosis, and cell cycle arrest were assessed in 4T1 cells. Tube formation assays were performed using HUVECs. Tumor progression, blood perfusion, and metastasis were evaluated in vivo using bioluminescence imaging, laser Doppler perfusion imaging (LDPI), and histological analyses. UA significantly inhibited 4T1 cell proliferation, induced G1-phase cell cycle arrest, and promoted apoptosis in a dose-dependent manner. In vivo, UA reduced tumor growth and metastasis, as evidenced by decreased bioluminescence signals and fewer metastatic lung lesions. UA also suppressed angiogenesis by inhibiting HUVEC tube formation and reducing local tumor perfusion in 4T1-bearing mice. Immunohistochemistry revealed that UA downregulated the expression of key adhesion- and angiogenesis-related molecules, including integrin β5, ESM-1, and ICAM-1, in both lung and tumor tissues. These findings demonstrate that UA effectively inhibits breast cancer progression and metastasis by targeting both tumor cells and endothelial function. Its ability to suppress angiogenesis and reduce adhesion molecule expression suggests UA is a promising candidate for anti-metastatic therapy in breast cancer.